Indomethacin external preparation

ABSTRACT

An object of the present invention is to provide an indomethacin external preparation that has an excellent use feeling and excellent absorbability and causes no phase separation into an oil layer and an aqueous layer, thus exhibiting satisfactory stability of preparation with time. Provided is an indomethacin external preparation containing: 0.1 to 3 wt % of indomethacin; 25 to 50 wt % of alcohol; 0.01 to 5 wt % of gelling agent; 5 to 30 wt % of oil component; 20 to 50 wt % of water; and 0.01 to 10 wt % of one or more components selected from the group consisting of glyceryl monostearate, sorbitan monostearate, stearyl alcohol, and polyethylene glycol monostearate.

RELATED APPLICATIONS

This application is the U.S. National Phase under 35 U.S.C. § 371 ofInternational Application PCT/JP2003/009273, filed Jul. 22, 2003, whichwas published in a language other than English, which claims priority ofJapanese Patent Application No. 2002-219315, filed Jul. 29, 2002.

TECHNICAL FIELD

The present invention relates to an indomethacin external preparationthat has an excellent use feeling and excellent absorbability ofindomethacin and undergoes no phase separation with time so that it canwell retain a stable state.

BACKGROUND ART

As external preparations containing indomethacin, those of variouspreparation forms such as a gel formulation, a cream formulation, aliquid formulation, and a poultice formulation are commerciallyavailable and those preparations have respective characteristicsinherent to the preparation forms.

For example, gel formulations contain a large amount of alcohol so thatthey dissolve indomethacin well therein and exhibit excellentabsorbability through a skin. However, when in use, they causeirregularities (a phenomenon in which a polymer collects like grime whenthe polymer is coated by rubbing) so that the formulations provide apoor use feeling. On the other hand, cream formulations are blended witha sufficient amount of oil so that after they are used, they do notstick, giving an excellent use feeling. However, because of insufficientsolubility of indomethacin therein, the cream formulations exhibit poorabsorbability of indomethacin through a skin as compared with that ofthe gel formulations.

Accordingly, it has been desired to develop a so-called gel-creamformulation that has advantages of both a gel formulation and of a creamformulation, i.e., a satisfactory use feeling and satisfactoryabsorbability of indomethacin through a skin and for this purpose manystudies have been made.

Usually, a surfactant is compounded in a cream formulation in order toprevent phase separation, i.e., separation into an oil layer and anaqueous layer. However, compounding a large amount of alcohol to a creamformulation results in the phase separation of the preparation into anoil layer and an aqueous layer with time since the alcohol inhibits theemulsifying action of the surfactant. In addition, compounding a gellingagent to a cream formulation in such an amount that irregularities willnot occur can hardly prevent such phase separation of the preparationwith time.

There have been known some prior art documents that report gel-creamformulations containing indomethacin, for example, JP 58-185514 A, JP59-227818 A, JP 57-126414 A, and JP 1-279831 A. However, the preparationdisclosed in JP 58-185514 A has an alcohol content of 10 wt % or less,so that the solubility and percutaneous absorbability of indomethacinare poor. The preparations disclosed in the other prior art documentsare unsatisfactory since they cause irregularities specific to gelformulations or phase separation of the preparations.

In view of those drawbacks, it has been demanded to provide anindomethacin external preparation that has an excellent use feeling andexcellent absorbability of indomethacin and that undergoes no phaseseparation of the preparation with time so that it can well retain astable state.

DISCLOSURE OF THE INVENTION

Accordingly, an object of the present invention is to provide anindomethacin external preparation that has an excellent use feeling andexcellent absorbability of indomethacin and that undergoes no phaseseparation of the preparation with time so that it can well retain astable state. More particularly, an object of the present invention isto provide an indomethacin external preparation that is compounded withoil component in an amount sufficient for the preparation to provide asatisfactory use feeling in spite of alcohol compounded in thepreparation in an amount sufficient for dissolving indomethacin and thatcauses no phase separation into an oil layer and an aqueous layer sothat it has excellent stability with time.

Taking into consideration the above-mentioned points, the inventors ofthe present invention have made extensive studies. As a result, theyhave found that compounding an indomethacin preparation containing 25 to50 wt % of alcohol sufficient for dissolving indomethacin therein and 5to 30 wt % of oil component sufficient for preventing the occurrence ofirregularities therein upon use or sticking thereof after use with 0.01to 10 wt % of one or more components selected from the group consistingof glyceryl monostearate, sorbitan monostearate, stearyl alcohol, andpolyethylene glycol monostearate prevents the phase separation with timeof the preparation, thereby accomplishing the present invention.

That is, according to the present invention, the following are provided:

(1) An indomethacin external preparation containing: 0.1 to 3 wt % ofindomethacin; 25 to 50 wt % of alcohol; 0.01 to 5 wt % of gelling agent;5 to 30 wt % of oil component; 20 to 50 wt % of water; and 0.01 to 10 wt% of one or more components selected from the group consisting ofglyceryl monostearate, sorbitan monostearate, stearyl alcohol, andpolyethylene glycol monostearate.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

An indomethacin external preparation of the present invention contains:0.1 to 3 wt % of indomethacin; 25 to 50 wt % of alcohol; 0.01 to 5 wt %of gelling agent; 5 to 30 wt % of oil component; 20 to 50 wt % of water;and 0.01 to 10 wt % of one or more components selected from the groupconsisting of glyceryl monostearate, sorbitan monostearate, stearylalcohol, and polyethylene glycol monostearate.

An indomethacin external preparation of the present invention has anexcellent use feeling and excellent absorbability and causes no phaseseparation into an oil layer and an aqueous layer, thus exhibitingsatisfactory stability of preparation with time.

The content of indomethacin in the preparation of the present inventionis usually 0.1 to 3 wt %, preferably 0.2 to 2 wt %, and particularlypreferably 0.5 to 1.5 wt % based on the total weight of the preparation.

In the present invention, the alcohol is preferably lower alcohol, andmore preferably alcohol having 1 to 3 carbon atoms. Examples of thealcohol include methanol, ethanol, isopropanol, and n-propanol. Amongthem, isopropanol is more preferred.

The content of alcohol is usually 25 to 50 wt %, preferably 30 to 50 wt%, and particularly preferably 30 to 40 wt % based on the total weightof the preparation. If the content of alcohol is less than 25 wt %,dissolution of indomethacin is insufficient so that the absorbability ofindomethacin becomes disadvantageously poor. On the other hand, thecontent of the alcohol above 50 wt % is undesirable since thepreparation becomes irritant to the skin and causes phase separationwith time of the preparation.

As examples of the gelling agent used in the present invention, acrylicpolymers such as carboxyvinyl polymer, cellulose polymers such ashydroxypropylmethylcellulose and ethylcellulose, polyvinyl alcohol, andthe like may be given.

The content of the gelling agent is usually 0.01 to 5 wt %, preferably0.5 to 5 wt %, and particularly preferably 0.5 to 2.5 wt % based on thetotal weight of the preparation.

As examples of oil component in the present invention, hydrocarbons suchas squalane and liquid paraffin, esters such as isopropyl myristate,diisopropyl adipate and octyldodecyl myristate, and the like may begiven.

The content of oil component is usually 5 to 30 wt %, preferably 7 to 30wt %, and particularly preferably 7 to 20 wt % based on the total weightof the preparation.

The content of the additional component(s), i.e., the one or morecomponents selected from the group consisting of glyceryl monostearate,sorbitan monostearate, stearyl alcohol, and polyethylene glycolmonostearate is usually 0.01 to 10 wt %, preferably 0.05 to 5 wt %, andparticularly preferably 0.1 to 5 wt % based on the total weight of thepreparation. The content of the additional component(s) described aboveis less than 0.01 wt % is undesirable since the phase separation withtime of the preparation cannot be prevented. On the other hand, thecontent of the additional component(s) above 10 wt % is also undesirablesince the consistency of the preparation increases to make thepreparation stiff, providing an unsatisfactory use feeling.

All the additional components usually have melting points of 40° C. orhigher and preferably 50° C. or higher. If the melting points are lowerthan 40° C., the phase separation with time of the preparation canhardly be prevented and such melting points are undesirable.

“Glyceryl monostearate” used in the present invention means a mixture ofα-glyceryl monostearate, β-glyceryl monostearate and other glycerylfatty ester(s), which is generally used as a base material. Examples ofcommercially available glyceryl monostearate include Nikkol MGS-A,MGS-B, MGS-F20, and MGS-F40 (trade names; manufactured by NikkoChemicals Co., Ltd.) and Rheodol MS-165, Rheodol MS-60 (trade names;manufactured by Kao Corporation.).

Further, the sorbitan monostearate used in the present invention is amonostearate obtained by esterification of the hydroxyl groups ofsorbitol anhydride with stearic acid. This is generally used as a basematerial. Examples of commercially available sorbitan monostearateinclude Nikkol SS-10, SS-10M (trade names; manufactured by NikkoChemicals Co., Ltd.) and Solgen 50 and Sorman S-300 (trade names;manufactured by Takeda Chemical Industries, Ltd.).

Further, as stearyl alcohol used in the present invention, for example,kalcohl (manufactured by Kao Corporation), Nikkol deodorization stearylalcohol (manufactured by Nikko Chamicals Co., Ltd.), lanette18(manufactured by Henkel Japan Ltd.), Conol30 S, Conol30 SS, Conol30 F(manufactured by New Japan Chemical Co., Ltd.), NAA-45, NAA-46(manufactured by NOF Corporation), and the like are on the market.

The polyethylene glycol monostearate used in the present invention is asubstance that is obtained by addition polymerization of stearic acidwith ethylene oxide or by esterification of polyethylene glycol withstearic acid and is generally used as a base material. For example,polyethylene glycol monostearate (manufactured by Nikko Chemicals Co.,Ltd.) is commercially available.

The content of water in the preparation of the present invention isusually 20 to 50 wt %, preferably 30 to 50 wt %, and particularlypreferably 40 to 50 wt % based on the total weight of the preparation.

Note that the indomethacin external preparation of the present inventionmay contain various optional components as desired. For example, it maycontain a neutralizing agent, a preservative agent, a stabilizing agent,a wetting agent and so forth.

Here, as the neutralizing agent, organic acids such as citric acid,phosphoric acid, tartaric acid and lactic acid, inorganic acids such ashydrochloric acid, alkali hydroxides such as sodium hydroxide, aminessuch as triethanolamine, diethanolamine, and diisopropanolamine, and thelike can be given.

Further, as the preserving agent, parahydroxybenzoates, benzalkoniumchloride, and the like can be given.

Further, as the stabilizing agent, sodium sulfite, sodium bisulfite,dibutylhydroxytoluene, butylhydroxyanisole, edetic acid, and the likecan be given.

Further, as the wetting agent, polyhydric alcohols such as glycerin,ethylene glycol, propylene glycol, oleyl alcohol, 1,3-butylene glycol,isopropylene glycol, polyethylene gylcol, and the like can be given.

The indomethacin external preparation of the present invention has a pHof usually 4 to 8 and preferably 5 to 7 from the viewpoints of thestability of indomethacin, prevention of skin irritation and so forth.

The indomethacin external preparation of the present invention can beprepared by a conventional method. For example, it can be produced byheating an oily base material that contains one or more componentsselected from the group consisting of glyceryl monostearate, sorbitanmonostearate, stearyl alcohol, and polyethylene glycol monostearate, anoil component, and the like at a temperature of 40° C. or higher tocompletely melt them, mixing the obtained melt with an aqueous basematerial having compounded therein a gelling agent, water and so forthuntil a homogeneous mixture is obtained, adding alcohol having dissolvedtherein indomethacin to the homogeneous mixture, and mixing theresultant until it becomes homogeneous.

EXAMPLES

Hereinafter, the present invention will be described concretely byexamples. However, it should not be considered that the presentinvention is limited to these examples.

Example 1

-   (1) 5 g of octyldodecyl myristate, 5 g of diisopropyl adipate, and 2    g of glyceryl monostearate (MGS-F20, trade name; manufactured by    Nikko Chemicals Co., Ltd.; melting point: 54-58° C.) were heated and    melted at about 70° C. and the whole was mixed until a homogeneous    mixture was obtained.-   (2) 1.5 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 36.0 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 0.8 g of diisopropanolamine was added to 5.2 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Example 2

-   (1) 5 g of octyldodecyl myristate, 5 g of diisopropyl adipate, and    0.5 g of sorbitan monostearate (NIKKOL SS-10M, trade name;    manufactured by Nikko Chemicals Co., Ltd.; melting point: 55-59° C.)    were heated and melted at about 70° C. and the whole was mixed until    a homogeneous mixture was obtained.-   (2) 1.5 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 37.5 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 0.8 g of diisopropanolamine was added to 5.2 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Example 3

-   (1) 5 g of octyldodecyl myristate, 5 g of diisopropyl adipate, and 2    g of stearyl alcohol (stearyl alcohol, trade name; manufactured by    Nikko Chemicals Co., Ltd.; melting point: 56-58° C.) were heated and    melted at about 70° C. and the whole was mixed until a homogeneous    mixture was obtained.-   (2) 1.5 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 36.0 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 0.8 g of diisopropanolamine was added to 5.2 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Example 4

-   (1) 5 g of octyldodecyl myristate, 5 g of diisopropyl adipate, and 2    g of polyethylene glycol monostearate (40 EO.) (NIKKOL MYS-40, trade    name; manufactured by Nikko Chemicals Co., Ltd.; melting point:    42-47° C.) were heated and melted at about 70° C. and the whole was    mixed until a homogeneous mixture was obtained.-   (2) 1.5 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 36.0 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 0.8 g of diisopropanolamine was added to 5.2 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Example 5

-   (1) 5 g of octyldodecyl myristate, 5 g of diisopropyl adipate, 0.5 g    of sorbitan monostearate, and 3.5 g of glyceryl monostearate were    heated and melted at about 70° C. and the whole was mixed until a    homogeneous mixture was obtained.-   (2) 1.0 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 34.5 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 0.5 g of diisopropanolamine was added to 5.5 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Comparative Example 1

-   (1) 5 g of octyldodecyl myristate and 5 g of diisopropyl adipate    were heated and melted at about 70° C. and the whole was mixed until    a homogeneous mixture was obtained.-   (2) 1.5 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 38.0 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 0.8 g of diisopropanolamine was added to 5.2 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Comparative Example 2

-   (1) 5 g of octyldodecyl myristate and 5 g of diisopropyl adipate,    were heated and melted at about 70° C. and the whole was mixed until    a homogeneous mixture was obtained.-   (2) 2 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 37.5 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 1 g of diisopropanolamine was added to 5 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish gel-cream preparation.

Comparative Example 3

-   (1) 5 g of octyldodecyl myristate, 5 g of diisopropyl adipate, and 2    g of polyoxyethylene (50) hydrogenated castor oil (HCO-50, trade    name; manufactured by Nikko Chemicals Co., Ltd.; melting point:    22-27° C.) were heated and melted at about 70° C. and the whole was    mixed until a homogeneous mixture was obtained.-   (2) 1.5 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 36.0 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 0.8 g of diisopropanolamine was added to 5.2 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Comparative Example 4

-   (1) 5 g of octyldodecyl myristate, 5 g of diisopropyl adipate, and 2    g of polysorbate 60 (NIKKOL TS-10, trade name; manufactured by Nikko    Chemicals Co., Ltd.; melting point: 30-34° C.) were heated and    melted at about 70° C. and the whole was mixed until a homogeneous    mixture was obtained.-   (2) 1.5 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 36.0 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 0.8 g of diisopropanolamine was added to 5.2 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Comparative Example 5

-   (1) 5 g of octyldodecyl myristate, 5 g of diisopropyl adipate, and 2    g of polysorbate 60 were heated and melted at about 70° C. and the    whole was mixed until a homogeneous mixture was obtained.-   (2) 2 g of carboxyvinyl polymer and 0.5 g of    hydroxypropylmethylcellulose 2910 were dispersed in 35.5 g of hot    water at about 70° C. and then the obtained dispersion was added to    the step (1), followed by well mixing the dispersion to emulsify it.-   (3) 1 g of indomethacin, 3 g of L-menthol and 1 g of polyethylene    glycol 400 were added to 36 g of isopropanol and the mixture was    stirred for dissolution. Then, the obtained solution was added to    the step (2) and the mixture was well mixed to uniformly disperse.-   (4) 1 g of an aqueous solution of 1% ETDA-2NA and 2 g of an aqueous    solution of 2% sodium bisulfite were added to the step (3) and the    mixture was well mixed.-   (5) 1 g of diisopropanolamine was added to 5 g of water and the    mixture was stirred for dissolution and the obtained solution was    added to the step (4). The mixture was well dispersed while it was    cooled to provide a pale yellowish white gel-cream preparation.

Test Example 1

To study phase separation stability of the produced preparation, therespective preparations of Examples 1 to 5 and Comparative Examples 1 to5 were filled in bottles, respectively, which were stored at 5° C. for 1month. Then, the state of the preparations after the storage wasobserved and evaluated by scoring those preparations in which no phaseseparation into an oil layer and an aqueous layer was observed as “o”and those preparations in which such phase separation was observed as“x”. Table 1 shows the results obtained.

TABLE 1 Com- Comparative Comparative Comparative Comparative parativeExample 1 Example 2 Example 3 Example 4 Example 5 Example 1 Example 2Example 3 Example 4 Example 5 Indomethacin 1 1 1 1 1 1 1 1 1 1Octyldodecyl 5 5 5 5 5 5 5 5 5 5 Myristate Diisopropyl 5 5 5 5 5 5 5 5 55 Adipate Carboxyvinyl 1.5 1.5 1.5 1.5 1.0 1.5 2.0 1.5 1.5 2.0 PolymerHydroxypropyl- 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Methylcellulose2910 L-menthol 3 3 3 3 3 3 3 3 3 3 Polyethylene 1 1 1 1 1 1 1 1 1 1glycol 400 Isopropanol 36 36 36 36 36 36 36 36 36 36 ETDA 2Na 0.01 0.010.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 sodium bisulfite 0.04 0.04 0.040.04 0.04 0.04 0.04 0.04 0.04 0.04 Diisopropanolamine 0.8 0.8 0.8 0.80.5 0.8 1.0 0.8 0.8 1.0 Water 44.2 45.7 44.2 44.2 43.0 46.2 45.5 44.244.2 43.5 Glyceryl 2 — — — 3.5 — — — — — monostearate Sorbitan — 0.5 — —0.5 — — — — — monostearate Stearyl alcohol — — 2 — — — — — — —Polyethylene glycol — — — 2 — — — — — — monostearate Polyoxyethylene — —— — — — — 2 — — (50) hydrogenated castor oil Polysorbate 60 — — — — — —— — 2 2 phase Separation ∘ ∘ ∘ ∘ ∘ x x x x x stability (stored for 1month - 5° C.)

From the results shown in Table 1, it can be seen that the preparationsof Examples 1 to 5, in which one or more of glyceryl monostearate,sorbitan monostearate, polyethylene glycol monostearate, and stearylalcohol were blended showed no phase separation and were stable but thepreparations of Comparative Examples 1 to 5 without those compoundsshowed phase separation.

Therefore, it was revealed that an increase in the compounding amount ofthe gelling agent as in the case of Comparative Example 2, compounding asurfactant having a melting point below 40° C. as in the cases ofComparative Examples 3 and 4, and an increase in the amount of thegelling agent and compounding a surfactant having a melting point below40° C. in combination as in the case of Comparative Example 5 were noteffective in preventing the phase separation of the preparations.

Test Example 2

To evaluate the use feeling of the preparations of the presentinvention, experiments were conducted by using a commercially availableindomethacin-compounded gel formulation and cream formulation as well asthe preparations of Examples 1 and 5. Evaluations of the use feelingwere made by checking the sticky feeling and occurrence ofirregularities when 0.5 g of each preparation was coated on an arm.

A preparation that gave no sticky feeling was assigned “o”, while apreparation that gave sticky feeling was assigned “x”. On the otherhand, a preparation in which no irregularity occurred was assigned “o”and a preparation in which irregularities occurred was assigned “x”Table 2 shows the results of evaluation of sticky feeling and Table 3shows the results of evaluation of irregularities.

TABLE 2 commercially commercially available available gel cream MonitorExample 1 Example 5 formulation formulation A ∘ ∘ x ∘ B ∘ ∘ x ∘ C ∘ ∘ ∘∘ D ∘ ∘ x ∘ E ∘ ∘ x ∘

TABLE 3 commercially commercially available available gel cream MonitorExample 1 Example 5 formulation formulation A ∘ ∘ x ∘ B ∘ ∘ x ∘ C ∘ ∘ x∘ D ∘ ∘ x ∘ E ∘ ∘ ∘ ∘

From the results shown in Tables 2 and 3, it can be seen that thepreparations of Examples 1 and 5 showed neither sticky feeling noroccurrence of irregularities, giving similar use feeling to that of acream formulation.

Test Example 3

To evaluate the absorbability of the preparations of the presentinvention, experiments on the absorbability of indomethacin through askin were conducted by using a commercially availableindomethacin-compounded gel formulation and cream formulation as well asthe preparations of Examples 1 and 5. Evaluation of the absorbabilitywas made by coating 0.5 g of each preparation on the shaven belly of arat to an area of 2 cm×2 cm and measuring the concentration ofindomethacin in the skin after 4 hours from the application of thepreparation. Table 4 shows the results obtained.

TABLE 4 commercially commercially available Exam- Exam- available gelcream ple 1 ple 5 formulation formulation Concentration 1144 1561 947189 of indomethacin in the skin (μg/g)

From the results shown in Table 4, it can be seen that the absorption ofindomethacin through the skin in the case of the preparations ofExamples 1 and 5 was higher than that of the commercially availablecream formulation and was equal to or higher than that of thecommercially available gel formulation.

From the above-mentioned results, it was confirmed that the preparationsof the present invention exhibited satisfactory absorbability ofindomethacin through the skin and provided an excellent use feeling.

INDUSTRIAL APPLICABILITY

According to the present invention, provided is an indomethacin externalpreparation that has an excellent use feeling and excellentabsorbability and causes no phase separation into an oil layer and anaqueous layer, thus exhibiting satisfactory stability of preparationwith time.

1. An indomethacin external preparation comprising: 0.1 to 3 wt % ofindomethacin; 25 to 50 wt % of alcohol; 0.01 to 5 wt % of gelling agent;7 to 30 wt % of oil component; 20 to 50 wt % of water; and 0.01 to 10 wt% of one or more components selected from the group consisting ofglyceryl monostearate, sorbitan monostearate, stearyl alcohol, andpolyethylene glycol monostearate (40EO), wherein the component selectedfrom the group consisting of glyceryl monostearate, sorbitanmonostearate, stearyl alcohol, and polyethylene glycol monostearate(40EO) has a melting point of 40° C. or higher.
 2. The indomethacinexternal preparation according to claim 1, wherein the selectedcomponent is glyceryl monostearate, sorbitan monostearate, or stearylalcohol.